Dibenzoazathiacycloalkane carboxamides and related oxa compounds



United States Patent Office 3,452,046 Patented June 24, 1969 3,452,046DIBENZOAZATHIACYCLOALKANE CARBOX- AMIDES AND RELATED OXA COMPOUNDS HarryL. Yale and Jack Bernstein, New Brunswick, N.J.,

assignors to E. R. Squibb & Sons, Inc., New York, N.Y., a corporation ofDelaware No Drawing. Filed Apr. 29, 1966, Ser. No. 546,193 Int. Cl. C07d99/10 US. Cl. 260-327 14 Claims This invention relates to novelphysiologically active substances of the formula wherein R representshydrogen, lower alkyl, or monocyclic aryl; R and R may be the same ordifferent and represent hydrogen, lower alkyl, and lower aralkyl; NR Rtaken together is a heterocyclic radical having the formula NR R inwhich X represents NH, O, or CH 1' represents 1, 2 or 3, and Rrepresents hydrogen, lower alkyl, lower alkoxy, hydroxy-lower alkyl,lower alkanoyloxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl anddi(lower alkyl)aminolower alkoxy-lower alkyl. These may be exemplifiedby R and R may be the same or dilferent and represent hydrogen, halogen,lower alkyl, cyclo lower alkyl, cyano,

lower haloalkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl,lower 'alkylsulfonyl, lower 'haloalkoxy, lower haloalkylthio, oramidosulfonyl, N,N- di -lower alkylamidosulfonyl; X represents oxygen orsulfur; m is 0 or 1; n is 0, 1 or 2; p is 0, 1 or 2; and the sum ofm'+m+p=l to 3, and salts thereof.

The terms lower alkyl, lower alkoxy, as employed herein, include bothstraight and branched chain radicals of less than eight carbon atoms.All four halogens are contemplated.

By monocyclic aryl radicals is meant phenyl and substituted phenylradicals such as lower alkylphenyl, e.g., 0-, m-, or p-tolyl,ethylpheny]; di-lower alkylphenyl, e.g., p-xylyl; lower alkoxyphenyl,e.g., methoxyphenyl; halophenyl, e.g., chlorophenyl, bromophenyl, etc.

As to the salts of the compounds of this invention, those coming Withinthe purview of this invention include the acid-addition salts,particularly the non-toxic acid-addition salts. Acids useful forpreparing the acid-addition salts, include inter alia, inorganic acids,such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid),sulfuric acid, nitric acid and phosphoric acid, and organic acids, suchas oxalic, maleic, fumaric, tartaric, citric, pamoic, acetic, andsuccinic acid.

Compounds of this invention are therapeutically active compounds whichare utilizable as anticonvulsants and antiepileptics for the treatmentof grand mal, petit mal, temporal lobe epilepsy, and trigeminalneuralgia. For these purposes, they may be administered orally orparenterally in such form as tablets, capsules, injectables, or the likeby incorporating the appropriate dosage of the compound with carriersaccording to the pharmaceutical practices.

The dose for humans would be initially about 200 mg., administered twoor three times daily. This level would be maintained for four to sixdays, and would then be increased to about 400 mg, two or three timesdaily, for

complete therapeutic maintenance.

The compounds of Formula I may be produced by reacting a compound of theformula with ammonia or an amine, either in the absence or presence ofsolvents like benzene, toluene, or ethanol, at ambient or elevatedtemperatures, i.e., 20-150 C., in a sealed zone.

The carbonyl chlorides of Formula II, which are used as startingmaterials, are produced by reacting a compound of the formula (III) HN-(CHR)m R 4 with phosgene in an inert solvent such as toluene or carbontetrachloride.

The compounds of Formula III may be prepared through any of severalprocesses, dependent upon the particular compound desired.

Compounds according to Formula III wherein X is sulfur, m equals 1, nequals 0, and p equals 1 are produced by reacting ana,a'-dihalo-o-xylene with an appropriately substitutedoaaminobenzenethiol in a solvent such as acetic acid orN,N-dimethylformamide at elevated temperatures.

Compounds according to Formula III wherein X is oxygen, m equals 1, nequals 0, and p equals l'are produced by reacting a lower alkylo-(halomethyl)benzoate with an o-nitrophenol to give a lower alkylo-(o-nitrophenoxymethyl)benzoate (IV), reducing (IV) by known means to alower alkyl o-(o-aminophenoxymethyl)benzoate (V), saponifying (V) byknown methods to an o-(oaminophenoxymethyl)benzoic acid (VI), cyclizing(VI) with a carbodiimide e.g., dicyclohexylcarbodiimide, to adibenzo[b,f] [1,4]oxazocin-11-one (VII), and, finally, reducing (VII)with lithium aluminum hydride or sodium borohydride to an11,l2-dihydrodibenz[b,f] [l,4]oxazo cine (VIII).

R and R are as hereinbefore defined:

-NO2 lower alkyl- C- N O 5 lower alkyl-02 0-- a a N 0 g lower-alkyl- 0 Cand 3 methoxy-Z-nitrophendl; and, (trifluoromethyl)-onitrophenols suchas 2-nitro-4-(trifluoromethyDphenol.

Among the suitable lower alkyl o-(halomethyDbenzoates (prepared from thelower alkyl o-methylbenzoates by reaction with sulfuryl chloride) arelower alkyl o-(halomethyl)halobenzoates such as ethyl6-chloro-o-(chloromethyl)benzoate, methyl 5--chloro-o-(chloromethyl)benzoate, 3-chloro o (chlordmethyhbenzoate,5-bromo-o- (chloromethyhbenzoate, and 4-bromo-o-(chloromethyl) benzoate;lower alkyl,cyano-o-(haloalkyl)benzoates such as methyl6-cyano-o-(chloromethynbenzoate (prepared Among the suitableo-nitrobenzyl mercaptans are (trifiuoromethyl)-o-nitrobenzyl mercaptanssuch as 4-(trifluoromethyl)-o-nitrobenzyl mercaptan (prepared by thesequence of reactions: 4-bromobenzotrifiuoride-94-(trifiuoromethyl)-phenylmagnesium bromide- 4 (trifluoromethyl)toluene-2-nit'ro-4 (trifluoromethyl)toluene 2- nitro-4 (trilluoromethyDbenzylbromide- 4 (trifluoromethyl) o-nitrobenzyl mercaptan; halo-o-nitrobenzylmercaptans such as 3-chloro-o-nitrobenzyl mercaptan (prepared by thebromination of 3-chloro-o-nitrotoluene to 3- chloro-o-nitrobenzylbromide and conversion, by known methods, to the mercaptan),4-ch-loro-o-nitrobenzyl mercaptan (prepared from 4-chloro-o-nitrotolueneas described above), and S-bromo-o-nitrobenzyl mercaptan (prepared asdescribed above from S-bromo-o-nitrbtoluene). p 7

Compounds according to Formula III- where X is oxygen and m, n and peach equals 1 and R and R are as hereinbefore defined (XI) are producedas shown directly above but substituting o-nitrobenzyl alcohol for theo-nitrobenzyl mercaptan used in that synthesis.

Among the suitable o-nitrobenzyl alcohols are(trifluoromethyl)-o-nitrobenzyl alcohols such as4-(trifiuoromethyl)-o-nitrobenzyl alcohol (prepared by the sequence ofreactions: 2-nitro-4-(trifluoromethyl)toluene- 2-nitro-4-(trifluoromethyl)benzoic acid 4-(trifluoromethyl) onitrobenzylalcohol); halo-o-nitrobenzyl alcohols such as 4-chloro-o-nitrobenzylalcohol (prepared by the sequence of reactions: 4-chloro-o-nitrotoluene-4-ch'loro o nitrobenzoic acid 4-chloro-o-nitrobenzyl alcohol); and, 5-bromo-o-nitrobenzyl alcohol (prepared by the above sequence of reactionsbut substituting S-bromo-o-nitrotoluene for the 4-chloro-o-nitrotoluene.

Compounds according to Formula III wherein X is oxygen or sulfur, mequals 1, n equals and p equals 0 are prepared by a series of reactionsas shown by the following equations, which for purposes ofexemplification, are directed to the thio product and wherein R, R and Rare as hereinbefore defined:

Among the suitable o-chloronitrobenzenes utilizable as initial reagentsin these reactions may be mentioned: o-chloronitrobenzene;halo-o-chloronitrobenzenes, such as 2,S-dichloronitrobenzene,2,4-dichloronitrobenzene, 2- chloro-S-fluoronitrobenzene, and2-chloro-4-fiuoronitrobenzene; (lower alkyl)-o-chloronitrobenzenes, suchas 5- (lower alkyl)-2-chloronitrobenzenes (e.g., 5 methyl 2-chloronitrobenzene, 5-ethyl-2 chloronitrobenzene, 5npropyl-2-chloronitrobenzene, and 5-n-hexyl-2-chloronitrobenzene); and4-(lower alkyl)-2-chloronitrobenzenes; (loweralkoxy)-o-chloronitrobenzenes, such as S-(loweralkoxy)-2-ch'loronitrobenzenes (e.g., S-methoxy-Z-chloronitrobenzene,S-ethoxy-2-chloronitrobenzene, S-n-propoxy- 2-chloronitrobenzene and5-n-hexyloxy-2-chloronitrobenzene); and (trifluoromethyl) ochloronitrobenzenes, such as 5-(trifiuoromethyl)-2-chloronitrobenzene,and 4- (trifluoromethyl)-2-chloronitrobenzene.

Among the suitable benzenethiols utilizable as initial reagents in thesereactions may be mentioned: benzenethiol; halobenzenethiols, such as2-chlorobenzenethiol, 4- chlorobenzenethiol, 2-fluorobenzenethiol,4-fluorobenzenethiol, and 2-bromobenzenethiol; (loweralkyl)benzenethiols, such as o-to'luenethiol, p-toluenethiol,Z-ethylben- Zenethiol, 4-n-propylbenzenethiol, and4-n-hexylbenzenethiol; (lower alkoxy)benzenethiols, such asZ-methoxybenzenethiol, 4-methoxybenzenethiol, 4-ethoxybenzenethiol, and4-propoxybenzenethiol; and (trifiuoromethyl) benzenethiols, such asZ-(trifiuoromethyl)benzenethiol and 4-(trifluoromethyl)benzenethiol.

Should the corresponding oxy compounds be desired, phenolic startingmaterials may be substituted for the above benzenethiols.

Suitable phenols utilizable as initial reagents in these reactions maybe mentioned: phenols; halophenols, such as Z-ch'lorophenol,4-chlorophenol, 2-fluorophenol, 4-fluorophenol, and 2-bromophenol;(lower alkyl)phenols such as o-cresol, p-cresol, Z-ethylphenyl,4-n-propylphenol, and 4-n-hexylphenol; (lower alkoxy)phenols, such as 2-methoxyphenol; 4-methoxyphenol, 4-ethoxyphenol, and 4-propoxyphenol; and(trifluoromethyl)phenols, such as 2-(trifiuoromethy1)phenol and4-(trifluoromethyl)phenol.

In the initial reaction of this process, the o-chloronitrobenzene isreacted with the benzenethiol, the reaction preferably being conductedin the presence of a condensation agent such as (e. g., sodiumhydroxide), whereby a corresponding 2-nitrophenyl phenyl sulfide(Compounds XII) is formed. The nitro group is then reduced to an amineby treatment with a reducing agent such as nascient hydrogen, which maybe formed in situ by the action of an electropositive metal on an acid,thereby forming the corresponding 2-(phenylthio)aniline derivative(Compounds V.)

If a final compound is desired which is unsubstituted in thell-position, the 2-(phenylthio)aniline is then treated with formic acidwhereby the corresponding 2-(phenylthio)formanilide (Compound XIV,wherein R is hydrogen) is produced. If, however, an ll-substitutedproduct is desired, the 2-(phenylthio)aniline is reacted with a loweralkanoyl halide or an aryl-carbonyl halide, whereby the correspondingacylated aniline derivative (Compound XIV, wherein R is alkyl or aryl)is formed. Among the suitable acyl halides utilizable in this step ofthe process may be mentioned lower alkanoyl chloride of at least twocarbon atoms, as exemplified by a-cetyl chloride, propionyl chloride,butyryl chloride and hexanoyl chloride, and monocyclic aryl carbonylchlorides, such as benzoyl chloride, o, m and p-toluyl chloride, ando,p-dimethylbenzoyl chloride.

Compound XIV is then cyclized by treatment with a mixture ofpolyphosphoric acid and phosphorus oxychloride at an elevatedtemperature (preferably about C. to about C.) to yield the correspondingdibenzo b,f] [1,4]thiazepine derivatives (Compound XV). Compound XV isthen reduced, as by treatment with a mixture of lithium aluminum hydrideand aluminum chloride, to yield the corresponding10,11-dihydrodibenzo[b,f][1,4] thiazepine derivatives (Compound XVI).

Compounds according to Formula III wherein m is 0, n is 1 and p is 0 areprepared alternatively by either of two series of. reactions as shown bythe following equations,

(trifluoromethoxy)2-bromobenzyl chloride and4-(trifluoromethoxy)2-bromobenzyl bromideand (dimethyl- CHa-O- Among thesuitable o-halobenzyl halides utilizable as initial reagents in reactionseries A may be mentioned: o-halobenzyl halides, such as o-bromobenzylbromide, ochlorobenzyl chloride and o-bromobenzyl chloride;haloo-halobenzyl halides, such as 2,5-dibromobenzyl bromide, 2,4-dibromobenzyl bromide, Z-bromo-S-fiuorobenzyl chloride,2-bromo-5-chlorobenzyl chloride, and 2brom0-4- fluorobenzyl chloride;(lower alkyl)-o-halobenzyl halides, such as S-(lower a1kyl)-2-haobenzy1halides, (e.g., 5- methyl-2-bromobenzyl chloride, S-ethyl-Z-bromobenzylbromide, S-n-propyl-Z-bromobenzyl bromide, and 5-nhexyl-2-chlorobenzylchloride); and 4-(lower alky1)-2- halo-benzyl halides: (loweralkoxy)-o-halo-benzyl halides such as S-(lower alkoxy)-2-halobenzylhalides (e.g., 5- methoxy 2 bromobenzyl bromide, S-ethoxy 2 bromobenzylchloride, 5-n-propoxy-2-bromobenzyl chloride, and5n-hexyloxy-Z-chlorobenzyl chloride) (trifiuoromethy1)- o-halobenzylhalides, such as 5-(trifluoromethyl)2-bromobenzyl chloride and4-(trifluoromethyl)-2-bromobenzyl bromide;(trifluoromethylmercapto)o-halobenzyl halides, such as5-(trifiuoromethylmercapto)2-bromobenzyl chloride and4-(trifluoromethylmercapto)2-bromobenzyl bromide;(trifluoromethoxy)-o-halobenzyl halides, such as 5-aminosulfonyD-ohalobenzyl halides, such as S-(dimethylaminosulfonyl)-2bromobenzy1 chloride and 4-(dimethylaminosulfonyl)2-bromobenzyl bromide.

Among the suit-able o-aminobenzenethiols utilizable as initial reagentsin reaction series A may be mentioned: o-aminobenzenethiol;halo-o-aminobenzenethiols, such as 5-chloro-2-aminobenzenethiol,4-chloro-2-aminobenzenethiol, S-fluoro-Z-arninobenzenethiol,4-fluoro-2-aminobenzenethiol, and 5 bromo 2 aminobenzenethiol; (loweralkyl)-o-aminobenzenethiols, such as 5-(lower alky1)-2-aminobenzenethiols (e.g., 5-methyl-2-aminobenzenethiol,5ethy1-2aminobenzenethiol, S-n-propyl-Z-aminobenzenethiol, and5-n-hexyl-2-aminobenzenethiol); and 4-(10wer alkyl)2-aminobenzenethiols;(lower alkoxy)-o-arninobenzenethiols, such as S-(loweralkoxy)o-aminobenzenethiols (e.g., S-methoxy-Z-aminobenzenethiol,5-ethoxy-2-aminobenzenethiol, S-n-propoxy-Z-aminobenzenethiol, andS-nhexyloxy-Z-aminobenzenethiol) and 4-(lower alk0Xy)-2-aminobenzenethiols) (trifluoromethyl)o-aminobenzenethiols, such asS-(trifiuoromethyl)2-aminobenzenethiol and4-(trifluoromethyl)2-aminobenzeuethiol; (trifiuoro- 'methoxy) oaminobenzenethiols, such as 5 (trifluoro methoxy) 2 aminobenzenethiol;(trifluoromethylmercapto)-o-aminobenzenethiols, such asS-(trifluoromethylmercapto) 2 aminobenzenethio; and N,N(dimethylaminosulfonyl) -o-aminobenzenethiols.

In the initial reaction of the process of reaction series A, theo-halobenzyl halide is reacted with an o-aminobenzenethiol, the reactionprefer-ably being conducted in the presence of a condensation agent,such as a base (e.g., sodium ethoxide), whereby a correspondingo-halobenzylo-aminophenylthioether (Compound XVII) is formed.

The aniline derivative (Compound XVII) is then treated with formic acidwhereby the corresponding 2- (o-halobenzylmerc-apto) formanilidederivative (Compound XVIII) is produced. Compound XVIII is then cyclizedby treatment with a basic reagent (e.g., potassium carbonate or sodiumcarbonate) in a solvent (e.g., N,N- dimethylformamide,N,N-dimethylacetamide, or nitrobenzene) at an elevated temperature,whereby the corresponding S-formyl 5,11 dihydrodibenzo[b,e][1,4]thiaZepine drivative (Compound XIX) is formed. The formamide isthen hydropolyzed, as by treatment with a base (e.g., sodium hydroxide)at an elevated temperature to yield the5,1l-dihydrodibenzene[b,e][l,4]thiazepine derivative (Compound XX).

Among the suitable o-halobenzyl halides utilizable as initial reagentsin reaction series B may be mentioned: o-halobenzyl halides, such aso-bromobenzyl bromide, o-chlorobenzyl chloride and o-bromobenzylchloride; haloo-halobenzyl halides, such as 2,5-dibromobenzyl bromide,2,4-dibromobenzyl bromide, 2bromo-5-fluorobenzyl chloride,2-bromo-5-chlorobenzyl chloride, and 2-bromo-4- fiuorobenzyl chloride;(lower alkyl)-o-halobenzyl halides, such as -(lower alkyl)-2-halobenzylhalides (e.g., S-rnethyl 2-bromobenzyl chloride, 5-ethyl-2-bromobenzylbromide, S-n-propyl-Z-bromobenzyl bromide and S-n-hexyl-Z- chlorobenzylchloride) and 4-(lower alky1)-2-halobenzyl halides; (loweralkoxy)-o-halobenzyl halides, such as 5- (lower alkoxy)-2-halobenzylhalides (e.g., S-methoxy-Z- bromobenzyl bromide, 5- ethoxy-2-bromobenzylchloride, S-n-propoxy-Z-bromobenzyl chloride, and S-n-hexyloxy-Z-chlorobenzyl chloride); (trifluoromethyl) o halobenzyl halides, such as5-(trifluoromethyl)-2-bromobenzyl chloride and4-(trifluoromethyl)-2-bromobenzy1 bromide;(trifluoromethylmercapto)-o-halobenzyl halides, such as5-(trifiuoromethylmercapto)-2-bromobenzyl chloride and 4(tritiuoromethylmercapto) 2-bromobenzyl bromide;(tritiuoromethoxy)-o-halobenzyl halides, such asS-(trifluoromethoxy)-2-bromobenzyl chloride and4-(trifluoromethoxy)-2-bromobenzyl bromide; and (N,N,-dimethylsulfonamido)-o-halobenzyl halides, such as5-(N,N-dimethylsulfonamido)-2-bromobenzyl chloride and 4-(N,N-dimethylsulfonamido)-2-bromobenzylbromide.

Among the suitable o-nitrophenols utilizable as initial reagents inreaction series B may be mentioned: o-nitrophenol; halo-o-nitrophenols,such as 5-chloro-2-nitrophenol, 4 chloro 2 nitrophenol, 5 fluoro 2nitrophenol, 4-fluoro-2-nitrophenol, and 5-bromo-2-nitrophenol; (loweralkyl)-o-nitrophenols, such as S-(lower alkyl)-2- nitrophenols (e.g.,S-methyl-Z-nitrophenol, 5-ethyl-2-nitrophenol, S-n-propyl-Z-nitrophenoland 5-n-hexyl-2-nitrophenol) and 4-(lower alkyl)-2-nitrophenols; loweralkoxy)-o-nitrophenols, such as 5-(lower alkoxy)-2-nitrophenols (e.g.,S-methoxy-Z-nitrophenol, 5-ethoxy2-nitrophe nol,S-n-propoxy-Z-nitrophenol and S-n-hexyloxy-Z-nitrophenol), and 4-(loweralkoxy)-2-nitrophenols; (trifiuoromethyl)-o-nitrophenols, such as5-(trifioromethyl)-2-nitrophenol and 4-(trifiuoromethyl)-2-nitrophenol;(trifluoromethoxy)-o-nitrophenols, such as 5-trifiuoromethoxy)-Z-nitrophenol; (trifluoromethylmercapto)-o-nitrophenols, such as5-(trifluoromethylmercapto)-2-nitropheno1s; andN,N-dimethylsulfonamido-o-nitrophenols.

In the initial reaction of the process of reaction series B, theo-halobenzyl halide is reacted with an o-nitrophenol, the reactionpreferably being conducted in the presence of a condensation agent, suchas a base (e.g., sodium hydroxide), whereby a correspondingo-halobenzyl-o-nitrophenyl ether (Compounds XXI) is formed. The nitrogroup is then reduced to an amine by treatment with a reducing agentsuch as nascient hydrogen, which may be formed in situ by the action ofan electropositive metal on an acid, thereby forming the corresponding2-(o-halobenzyloxy)aniline derivative (compound XXII).

The aniline derivative (Compound XXII) is then treated with formic acidwhereby the corresponding 2- (o -halobenzyloxy)formanilide derivative(Compound XXIII) is produced. Compound XXIII is then cyclized bytreatment with a basic reagent (e.g., potassium carbonate or sodiumcarbonate) in a solvent (e.g., N,N-dimethyl formamide,N,N-dimethylacetamide, or nitrobenzene) at an elevated temperature,whereby the corresponding 5-formyl-5,11 dihydrodibenz[b,e][1,4]oxazepine derivative (Compound XXIV) is formed. The formamide isthen hydrolyzed, as by treatment with a base (e.g., sodium hydroxide) atan elevated temperature to yield the 5,11-dihydrodibenz[b,e][1,4]oxazepine derivative (Compound XXV).

Reaction series A and B may be employed interchangeably in thepreparation of the thio or oxy compounds. However, as illustrated, it ispreferable to employ reaction series A in the preparation of the thiocompounds and reaction series B in the preparation of the oxy compounds.

Compounds according to Formula III wherein n is 2 and m and p are each 0may be prepared by the reaction sequences A and B set forth above,substituting an ohalophenethyl halide for the o-halobenzyl halideemployed therein.

The compounds according to Formula III wherein X is oxygen, m is 1, n is2 and p is 0 are prepared by a series of reactions shown by thefollowing equations:

In the initial reaction, a lower alkyl ester of salicyclic acid istreated with a 2-nitrophenethyl halide under alkaline conditions. The2-(2-nitrophenethoxy)benzoic acid ester thus obtained (Compounds XXVI)is reduced to the corresponding amino derivative (Compound XXVII) bycatalytic reduction or other standard reduction methods, and the esterhydrolyzed with dilute aqueous alkali to yield the desiredZ-(Z-aminophenethoxy)benzoic acid (Comopund XXVIII). This acid is thenring-closed by treatment with dicyclohexylcarbodiimide to yield adibenz[b,f][l,5]oxazonin-6-one (Compound XXIX) which is reduced bytreatment with lithium aluminum hydride to a dibenz[b,f] [l,5]oxazonine(Compound XXX).

The compounds of Formula III in which X is sulfur, m is l, n is 2 and pis 0, are obtained by treating a lower alkyl ester of 2-mercaptobenzoicacid with a 2-nitrophenethyl halide under alkaline conditions and the2-(2- nitrophenethylmercapto)benzoic acid ester carried through theseries of reactions outlined above for the preparation of thecorresponding oxygen analog.

The compounds according to Formula HI wherein X is oxygen, m is 0, n isl and p is 2 are prepared by a series of reactions shown by thefollowing equations:

HOCHaCHz- 12 pound XXXIV with aqueous alkali yields the desireddibenz[c,f] [1,5]oxazone (Compound XXXV).

The compounds of Formula III in which X is sulfur, in is 0, n is l and pis 2, the sum of m, n and p being 3, are obtained by treating aZ-bromophenethyl mercaptan with a 2-nitrobenzy bromide to obtain a2-bromophenethyl sulfide and carrying out the series of reactionsoutlined above for the corresponding oxygen analog.

EXAMPLE 1 2-chloro-11,l2-dihydro-6H-dibenzo[b,f] [1,41thiazocine-12-carboxamide (a) Under nitrogen, a solution of 5 g. of sodiumhydroxide in 250 ml. of water is added to a stirred suspensi n of 25.5g. of 2-amino-4-chlorobenzenethiol hydrochloride in 800 ml. of hexane.The base is dissolved in the hexane; the hexane is filtered, dried undernitrogen, and the hexane is removed via a flash evaporator to give 14.2g. of 2-amino-4-chlorobenzenethiol, M.P. about 4446.

(b) A solution of 21 g. of a,a'-dibromo-o-xylene in 300 ml. of drydimethylformamide is stirred at under nitrogen. To this at 95-105 isadded 13 g. of 2-amino-4- chlorobenzenethiol in 250 ml. ofdimethylformamide for 15 minutes. After the addition, stirring iscontinued at -105" for one hour. The dimethylformamide is removed andthe residue recrystallized from ethanol to give 2-chloro-1 1,12-dihydro6H dibenzo b,f] [1,4] thiazocine hydrobromide, M.P. about 210-2l2 (dec.)

(c) A solution of 4.0 g. of 85% potassium hydroxide in 40 ml. of wateris added to a stirred suspension of 15 g. of the hydrobromide in 200 ml.of ether. The base extracts into the ether. The ether is washed, dried,concentrated, and the residue is recrystallized from cyclohexane to give2-chloro-1l,12-dihydro-6H-dibenzo[b,f][l,4]thiazocine.

(d) At 10-15 a solution of 4.0 g. of phosgene in 30 ml. of toluene isadded during 20 minutes to a stirred solution of 5.3 g. of2-chloro-11,12-dihydro-6H-dibenzo [b,f]{1,4]thiazocine and 4.0 g. oftriethylamine in 175 ml. of toluene. After the addition, stirring iscontinued for two hours. The reaction mixture is filtered, the filtrateis concentrated, and the residue taken up in ether. The filtered ethersolution is again concentrated to give 2-chloro-11,12-dihydro6H-dibenzo[bi] [l,4]thiazocine 12 carbonyl chloride.

(e) 2-chloro-1l,l2 dihydro 6H dibenzo[b,f] [1,4]- thiazocine-lZ-carbonylchloride, 3.6 g., and 50 ml. of 3.2 N ethanolic ammonia are heated at-125 for 30 hours. After cooling, the reaction is concentrated todryness, the solid is washed with water, dried, and recrystallized fromacetonitrile to give 7-chloro-ll,12-dihydro- 6H-dibenzo[b,f][1,41thiazocine 12 carboxamide, M.P. about 223-225 (dec.).

EXAMPLE 2 N,N-dimethyl-2-chloro1 1,12-dihydro-6H-dibenzo- [b,f] [1,4]thiazocine-12-carboxamide By substituting 50 ml. of 4.7 N ethanolicdimethylamine for the ethanolic ammonia in Example 1, there is obtainedN,N-dimethyl-2-chloro-11,12-dihydro-6H-dibenzo [b,f]1,4]thiazocine-12-carboxamide.

EXAMPLE 3 N-(2-propyl)-2-chloro-11,12-dihydro 6H-dibenzo[b,f]

[ 1,4] thiazocine- 12-carb0xamide By substituting 50 ml. of 5.2 Nethanolic 2-propylamine for the ethanolic ammonia in Example 1, there isobtained N (2-propyl)-2-chloro-l1,12-dihydro-6H-dibenzo [b,f][1,4]thiazocine-l2-carboxamide.

13 EXAMPLE 4 (a) By substituting 16.6 g. of 2-amino-4-bromobenzenethiolfor the 2-amino-4-chlorobenzenethiol in Example l(b), there is obtained2-bromo-l1,12-dihydro-6H- dibenzo [b,f] [1,4] thiazocine.

(b) By substituting 6.2 g. of the product from (a) for the2-chloro-10,11-dihydro-6H-dibenzo[b,f] [1,4] thiazocine in Example 1(d),there is obtained 2-bromo-11,12- dihydro-6H-dibenzo-[b,f] [1,4]thiazocine 12-carbonyl chloride.

(c) By substituting 4.1 g. of the product from (g) for the2-chloro-10,11-dihydro-6H dibenzo [b,f] [1,4]thiazocine-12-carbonylchloride and 2.2 g. of N-methylpiperazine in 50 ml. absolute ethanol forthe ethanolic ammonia in Example 1(e), there is obtained2-bromo-l2-[1-(4- methylpiperazinyl)carbonyl] 11,12 dihydro-6H-dibenzo[b,f] [1,4] thiazocine.

EXAMPLE 5 N,N-dibenzyl-2-bromo-11,12 dihydro-6H-dibenzo [b,f] [1,4]thiazocine- 12-carboxamide By substituting 4.35 g. of N,N-dibenzylaminefor the N- methylpiperazine in Example 4(c), there is obtained N,N-dibenzyl-Z-bromo-l1,12-dihydro-6H dibenzo[b,f] [1,4]thiazocine-12-carboxamide.

EXAMPLE 6 2-bromo- 12- 1 (4-methylhomopiperazinyl carbonyl] -1 1,12-dihydro-6H-dibenzo [b,f] [1,4] thiazocine By substituting 2.51 g. of4-methylhomopiperazine for the N-methylpiperazine in Example 4(c), thereis obtained 2-bromo-12-[ l- (4-methyll1omopiperazinyl) carbonyl] -1 1,12-dihydro-6H-dibenzo [b,f] [1,4] thiazocine. This product, in 10volumes of anhydrous ether, is cooled and treated with one equivalent ofhydrogen chloride in anhydrous ether to give a precipitate of thehydrochloride. This is filtered and recrystallized from acetonitrile togive the pure product.

EXAMPLE 7 11,12-dihydro-6H dibenzo[b,f][1,4] thiazocine-12-carboxamide(a) To a solution of 13.2 g. of a,a-dibromo-0-xylene in 250 ml. ofdimethylformamide at 100 under nitrogen is added dropwise a solution of6.2 g. of o-aminobenzenethiol in 150 ml. of dimethylformamide. Followingthe addition, the reaction mixture is stirred for an additional 0.5 hourat 90-95 and the dimethylformamide is removed to give11,12-dihydro-6H-dibenzo[b,f][ 1,4]thiazocine hydrobromide.

(b) To 10 g. of 85% potassium hydroxide in 250ml. of water is added at100, g. of the above hydrobromide salt. The mixture is stirred at 100until the solid in suspension is converted to an oil. After cooling, theoil is extracted into ether, the ether solution is washed, dried andconcentrated to give 14.5 g. of 11,12-dihydro-6H-dibenzo[b,f][1,4]-thiazocine, m.p. about 102104 after recrystallization fromcyclohexane.

(c) To 5.7 g. of the product from (b), 5 g. of triethylamine and 75 ml.of anhydrous toluene at 5 is added a solution of 5 g. of phosgene in 36ml. of toluene at 510. After the addition, stirring is continued at roomtemperature for 2 hours. The reaction mixture is filtered, the filtrateis concentrated and the residue is recrystallized from cyclohexane togive 11,12-dihydro-6H-dibenzo[b,f] [1,4]thiazocine, M.P. about 144-145(d) A suspension of 3.5 g. of the product from (c) in 50 ml. of 3.2 Nalcoholic ammonia is heated at 110- 120 for 20 hours in a sealed tube.After cooling the solid is filtered. The filtrate is concentrated andthe residue is combined with the above solid, Washed with water, andrecrystallized from acetonitrile to give 11,12-

dihydro-6H dibenzo [b,f] [1,4] thiazocine-12-carboxamide, M.P. about213-215.

EXAMPLE 8 2-propyl-l1,12-dihydro 6H-dibenzo[b,f][l,4]-thiazocine-12-carboxamide By replacing theo-aminobenzenethiol with o-amino-ppropyl-benzenethiol (prepared by thereaction sequence: p-propylaniline 2-amino S-propylsulfonyl chlorideoamino-p-propylbenzene-thiol), there is obtained, by following theprocedure of Example 7, 2-propyl-11,l2-dihydro-6H-dibenzo[b,f] 1,4]thiazocine-12-carboxamide.

EXAMPLE 9 1 1,12-dihydro- (trifluoromethyl)-6H-dibenzo [b,f] [1,4]thiazocine-12-carboxamide (a) A solution of 4 g. of phosgene in 30 ml.of toluene is added over a period of 20 minutes to a stirred, ice cooledsolution of 5.9- g. of 11,12-dihydro-2-(trifluoromethyl)6H-dibenzo[b,f][1,4] thiazocine and 4 g. of triethylamine in 175 ml. ofanhydrous toluene at 5-10". After the addition, stirring is continued atroom temperature for 2 hours. The mixture is filtered, the filtrate isconcentrated and the residue taken up in ether. The filtered ethersolution is concentrated to give 6 g. of 11,12-dihydro-2-(trifluoromethyl) 6H-dibenzo[b,f][l,4]-thiazocine-IZ-carbonyl chloride, M.P. about 157-159 afterrecrystallization from cyclohexane.

(b) A suspension of 3.6 g. of the product from (a) in 50 ml. of 3.2 Nethanolic ammonia is heated at 120125 in a sealed tube for 30 hours.After cooling, the solid is filtered. An additional 2 g. of solid isrecovered from the filtrate. The solid is washed with water, dried, andrecrystallized from acetonitrile to give 2.1 g. of11,12-dihydro-2-(trifiuoromethyl)-6Hdibenzo[b,f][1,4]thiazocine-12-carboxamide, M.P. about 253-255 EXAMPLE10 5,11-dihydrodibenzo[b,e] [1,4] thiazepine-S-carboxamide A solutioncontaining 8.2 g. of 5,1l-dihydrodibenzo [b,e][1,4]thiazepine, 2.8 g. ofdry pyridine and ml. of dry toluene is cooled to 10 and treated dropwisewith 47 ml. of a 15% solution of phosgene in dry toluene. Subsequently,the reaction mixture is kept 2 hours at -10, 4 hours at 0, and thenallowed to warm to room temperature overnight. The toluene solution isdecanted, cooled, mixed with 120 ml. of 2.9 N ethanolic ammonia, sealedinto tubes, and heated 18 hours at The cooled tubes are opened, theethanol-toluene solution is decanted, and concentrated to dryness invacuo. The residue is heated to boiling with 100 ml. of benzene and thebenzene solution poured on a column of activated alumina. Elution of thecolumn first with benzene and then with 2-propanol gives a solidproduct. This solid is again chromatographed on alumina and the columnis eluted first with benzene and finally with 2-propanol to give5,11-dihydrodibenzo[b,e][1,4]thiazepine S-carboxamide, M.P. about215-217.

EXAMPLE 1 l 5,1 l-dihydrodibenz[b,e] [1,4] oxazepine-S-carboxamide Bysubstituting 8.2 g. of 5,11-dihydrodibenz [b,e] [1,4]- oxazepine for the5,11-dihydrodibenzo[b,e] [1,4]thiazepine in Example 10, there isobtained 5,11-dihydrodibenz [b,e] [1,4]-oxazepine-5-carboxamide, M.P.about 201- 203.

EXAMPLE 12 7-prop oxy-5,1 1-dihydrodibenz[b,e] 1,4] oxazepine-S-carboxamide By replacing the 5 ,1l-dihydrodibenZ[b,e] [1,4]oxazepinewith 7 propoxy-5,11-dihydr0dibenz[b,e] [l,4]0xazepine, there is obtainedby a similar procedure, 7-propoxy-5,l1- dihydrodibenz[b,e] [1,4]-oxazepine-5-carboxamide.

15 The 7-propoxy-5,l l-dihydrodibenz [b,e] [l,4]oxazepine is preparedfrom 4-propoxyphenol, by nitration, to a 4- propoxy-o-nitrophenol. Thelatter compound, by the procedure of J. Med. Chem. 7, 609 (1964) gives7-propoxy- 5,11-dihydrodibenz[b,e] [1,4]-xazepine.

EXAMPLE l3 7-chl0ro-S,l 1-dihydrodibenz[b,e] [1,4]oxazepine-5-carboxamide By substituting 8.2 g. of 7-chlor0-5,1l-dihydrodibenz [b,e][1,4] oxazepine for the 5,11 dihydrodibenzothiazepine in Example 10,there is obtained 7chloro-5,l1-dihydrodibenz[b,e] [1,4]oxazepine-5carboxamide, M.P. about 191-193 EXAMPLE 148-chloro-10,11-dihydrodibenzo[b,f] [1,4]thiazepine-10- carboxamideEXAMPLE N,N-diethyl-11-phenyl-5,11-dihydrodibenzo[b,e] [1,4]thiazepine-S-carboxamide By substituting 8.5 g. ofl1-phenyl-5,ll-dihydrodibenzo [b,e] [l,4]thiazepine for the5,11-dihydrodibenzo[b,e] [1, 4]thiazepine and 120 ml. of 3.1 N ethanolicdiethylamine for the ethanolic ammonia in Example 10, there is obtainedN,N diethyl-11-phenyl-5,11-dihydrodibenzo[b,e]

[1,4] thiazepine-S-carboxamide.

EXAMPLE l6 5-( l-piperidylcarbonyl) -10,12-dihydro-5H- dibenz[c,f,] [1,5oxazocine (a) To 4.2 g. of 50% NaOH in 195 ml. of anhydrous ether, undernitrogen, is added 13.0 g. of o-nitrobenzyl alcohol in 260 ml. ofanhydrous ether. To this suspension at 0 is added 21.6 g. ofo-bromobenzyl bromide in ml. of anhydrous dimethyl formamide. Themixture is allowed to warm to room temperature spontaneously and after 4hours, treated with water. The mixture is worked up to give 11.5 g. ofo-bromobenzyl-o-nitrobenzyl ether, M.P. about 99.5-101.0.

(b) To the product from (a), 4.5 g. in 100 ml. of 95% ethanol at 70 isadded in one portion, a slurry of 20.0 g. of FeSO -2H O in 300 ml. of a1:1 mixture of concentrated (28-30%; sp. g. 0.9) ammonium hydroxide andwater. Subsequently, the mixture is refluxed for 5.5 hours and filteredhot. From the filtrate, there is obtained 3.35 g. ofo-[o-bromobenzyloxymethyl]-aniline, M.P. about 55.5-56.5".

(c) The product from (b), 32 g. and 300 ml. of 98- 100% formic acid arerefluxed for 5 hours and then concentrated to dryness in vacuo to giveo-[o-bromobenzyloxymethyl] form anilide.

(d) To 2.0 g. copper bronze, 24.5 g. of micronized anhydrous K CO and300 ml. of anhydrous dimethyl formamide, under reflux, is added slowly asolution of 32.0 g. of the product from (c) in 300 ml. of anhydrousdimethyl formamide. The mixture is refluxed for 1 hour, an additional 10g. of micronized anhydrous K CO is added, the reflux continued for 2additional hours, and the hot mixture is filtered. The filtrate isconcentrated to dryness in vacuo; the residue, cc. 25% aqueous NaOH and300 ml. of 95% ethanol, are refluxed for 1 hour and again concentratedto dryness in vacuo. From 16 the residue there is isolated10,12-dihydro-5H-dibenz[c,f] [1,5 oxazocine.

(e) By substituting 8.7 g. of the product from (d) for the5,11-dlhydrodibenzo[b,e] [1,4]thiazepine, 8.5 g. of piperidine and 50ml. of absolute ethanol for the ethanolic ammonia in Example 10, thereis obtained 5-(l-piperidylcarbonyl) 10,12 dihydro-5H-dibenz[c,f][l5]oxazocine. Purification of this material is effected byrecrystallization from petroleum ether.

EXAMPLE l7 5-{ 1- [4-(Z-hydroxyethyl)piperazinyl] carbonyl}- 10,12-

dihydro-S H-dibenzo [c,f,] [1,5] thiazocine (a) By substituting 14.3 g.of o-nitrobenzyl mercaptan for the o-nitrobenzyl alcohol in Example16(a) and then following the procedures of Example 16(1)), (c), and (d),there is obtained 10,1Z-dihydro-SH-dibenzo[c,f,] [1,51thiazocine.

(b) By substituting 9.0 g. of the product from Example 16(d) for the10,12-dihydro 5H dibenz[c,f] 1,4]oxazocine, 13.0 g. of2-hydroxyethylpiperazine and 50 ml. of absolute ethanol for theethanolic ammonia in Example 10, there is obtained5-{1-[4-(2-hydroxyethyl)piperazinyl]carbonyl} 10,12dihydro-5H-dibenzo[c,f][1,5]thiazocine.

EXAMPLE 18 12-(1-pyrrolidylcarbonyl)-1 1,12-dihydro-6H- dibenzo [b,f][1,4] -thiazocine By substituting 7.1 g. of pyrrolidine and 50 ml. ofabsolute ethanol for the alcoholic ammonia in Example 7 (d), there isobtained 12-(1-pyrr0lidylcarbonyl)-11,12- dihydro-GH-dibenzo [b,f] [1,4]thiazocine.

EXAMPLE 19 12- (4-morpholinylcarbonyl 1 1, 12-dihydro-6H- dibenzo [b,f[1,4] -thiaz0cine By substituting 8.7 g. of morpholine and 50 ml. ofabsolute ethanol for the alcoholic ammonia in Example 7(d), there isobtained 12-(4-morpholinylcarbonyl)-1 1,12- dihydro-6H[b,f] [1,4]thiazocine.

EXAMPLE 2O N-methyl-3-bromo-7-propoxy-5,1 1-dihydrodibenz[b,e] 1,4]oxazepine-S-carboxamide (a) Employing the procedure of J. Med. Chem. 7,609 (1964) with 2,4-dibromobenzyl bromide and 4-propoxyo-nitrophenol,there is obtained 3-bromo-7-propoxy-5,11- dihydrodibenz[b,e] [1,4]oxazepine.

(b) By substituting 6.68 g. of the product from (a) for the2-chloro-l1,12-dihydro-6H-dibenzo[b,f] [1,4]thiazocine in Example 1(d),there is obtained 3-bromo-7- propoxy 5,11 dihydrodibenz-[b,e][l,4]oxazepine 5 carbonyl chloride.

(o) By substituting 4.3 g. of the product from (b) for the 2chloro-11,l2 dihydro 6H dibenzo [bi] [1,4]thiazocine and 50 ml. of 3.2 Nethanolic methylamine for the ethanolic ammonia in Example 1(e), thereis obtained N-methy1-3-bromo 7 propoxy-S,11-dihydrodibenz[b,e] [1,4]oxazepine-S-carboxamide.

EXAMPLE 21 5,6,12,13-tetrahydrodibenz[b,f] [1,5] oxazonine-S-carboxamide (a) To a solution of 2.3 g. of sodium in 250 ml. ofanhydrous ethanol is added 16.6 g. of ethyl salicylate. A solution of23.0 g. of 2-nitrophenethyl bromide in 250 ml. of anhydrous ethanol isadded dropwise with vigorous stirring. After the addition is completed,the reaction mixture is heated to gentle reflux, with stirring, untilthe reaction mixture is no longer alkaline. The mixture is concentratedin vacuo to remove the alcohol and the residue is extracted into ether.The ether extract is washed 17 with water, dried, and concentrated toyield ethyl 2-(0- nitrophenethoxy) benzoate.

(b) To a solution of g. of the product from (a) in 200 ml. of ethanol,is added 0.5 g. of palladium on carbon catalyst and the mixture shakenwith hydrogen at 50 p.s.i. until the theoretical quantity of hydrogenhas reacted. The mixture is filtered and the ethanol removed in vacuo toyieldethyl 2-(o-aminophenethoxy)benzoate. The product is dissolved inanhydrous ether, treated with an ethereal solution of hydrogen chlorideand the precipitated hydrochloride is obtained by filtration. It isrecrystallized from an alcohol-ether mixture. An aqueous solution of thehydrochloride is treated with sodium bicarbonate and the liberated baseis extracted into ether. The ether solution is dried and concentrated toyield ethyl 2-(o-aminophenethoxy)benzoate.

(c) A mixture of 14.3 g. of the product from (b), 10 g. of sodiumhydroxide and 250 ml. of 50% aqueous alcohol is refluxed for 4 hours.The alcohol is distilled, the aqueous residue cooled, and extracted withether. The aqueous solution is neutralized with 10% hydrochloric acidand the precipitated 2-(o-aminophenethoxy)benzoic acid is filtered,airdried and recrystallized from aqueous alcohol.

(d) To a mixture of 15.3 g. of the product from (c) in 750 ml. ofanhydrous ethyl acetate is added a solution of 12.3 g. ofdicyclohexylcarbodiimide in 250 ml. of ethyl acetate. The reactionmixture is stirred vigorously, under nitrogen, for 36 hours and is thenfiltered.

The filtrate is concentrated in vacuo, the residue triturated with asmall amount of cold ethyl acetate, and filtered. The12,13-dihydrodibenz[b,f][1,5]oxazonine- (5H)-one thus obtained may becrystallized from acetonitrile.

(e) To a solution of 1.6 g. of lithium aluminum hydride and 500 ml. ofanhydrous ether is added a solution of 2.3 g. of the product from (d) in1,000 ml. of anhydrous ether. The reaction mixture is allowed to stir atroom temperature for 24 hours. To the reaction mixture is added dropWisewith vigorous stirring 6 ml. of water, followed by 5 ml. of 10% aqueoussodium hydroxide. The reaction mixture is filtered and the filtratedried, concentrated, and the residue recrystallized from hexane to yield5,6,12,13-tetrahydrodibenz[b,f] [1,51oxazonine.

(f) A solution of 4 g. of phosgene in 30 ml. of toluene is addeddropwise, with vigorous stirring, to a cooled solution of 4.5 g. of theproduct from (e) and 4 g. of triethylamine in 175 ml. of anhydroustoluene. After the addition is complete, the reaction mixture is stirredfor 2 hours at room temperature and filtered. The filtrate isconcentrated in vacuo, the residue is extracted into ether, the ethersolution is filtered, and the filtrate is concentrated to give5,6,12,13-tetrahydrodibenz[b,t][1,5]oxazonine-S-carbonyl chloride.

(g) A mixture of 2.9 g. of the product from (f) and 50 ml. of a 3.2 Nethanolic ammonia solution is heated in a sealed tube at 125 for 30hours. The contents of the cooled tube are concentrated, the residuesuspended in 100 ml. of water, filtered, and the solid crystallized fromacetonitrile to yield 5,6,12,13-tetrahydrodibenz[b,f]- [1,5 1oxazonine-S-carboxamide.

EXAMPLE 22 5,6,12,13-tetrahydrodibenz[b,f] [1,5]thiazonine-5-carboxamide Following the procedure of Example 21, but substituting anequivalent amount of methyl o-mercaptobenzoate for the ethyl salicylate,there is obtained 5,6,12,13-tetrahydrodibenz[b,f] [1,5thiazonine-S-carboxamide.

EXAMPLE 23 5, l0,12,13-tetrahydrodibenz[c,f] [1,5] oxazonine-S-carboxamide (a) To a solution of 20.1 g. of o-bromophenethyl alcohol in200 ml. of anhydrous toluene is added 4 g. of sodamide and the mixturestirred vigorously with gentle warming until the evolution of ammonia isessentially complete. To the cooled mixture is added dropwise and withvigorous stirring a solution of 21.6 g. of o-nitrobenzyl bromide inanhydrous toluene. The reaction mixture is stirred at room temperaturefor 2 hours and fluxed for one hour, cooled, neutralized with aqueoushydrochloric acid, and concentrated to dryness. The residue istriturated with water, dried, and recrystallized from hexane to yieldthe desired 5,10,12,13 tetrahydrodibenz[c,f] [1,5]oxa zonine.

(f) A solution of 4 g. of phosgene in 30 ml. of toluene is addeddropwise, with vigorous stirring to a cooled solution of 4.5 g. of theproduct from (e) and 4.0 g. of triethylamine in 175 ml. of anhydroustoluene. After the addition is complete, the mixture is stirred for 2hours at room temperature, and filtered. The filtrate is concentrated invacuo and the residue dissolved in ether. The solution is filtered andconcentrated to give 5,10,12,13-tetrahydrodibenz[c,f][1,5]oxazonine-5-carbonyl chloride.

(g) A mixture of 2.9 g. of the product from (f) and 50 ml. of a 3.2 Nethanolic ammonia solution is heated in a sealed tube at 125 for 30hours. The contents of the cooled tube are concentrated and the residuesuspended in 100 ml. of water. The solid is filtered, dried, andrecrystallized from acetonitrile to yield5,10,12,13-tetrahydrodibenz[c,f] [1,5 oxazonine-S-carboxamide.

EXAMPLE 24 5,10,12,13-tetrahydrodibenz[c,f] [1,5 thiazonine-S-carboxamide (a) A mixture of 132 g. of 2-bromophenethyl bromide, 38'g. of thiourea and 250 ml. of ethanol is refluxed for 3 hours. Asolution of 30 g. of sodium hydroxide in 300 ml. of Water is added andthe mixture is refluxed for 2 hours. The aqueous layer is separated,acidified and extracted with benzene. The ibenzene extract is combinedwith the original organic layer, and washed with water. The benzenesolution is dried, the solvent removed, and the residue distilled invacuo to yield the desired 2-bromophenethyl mercaptan.

(b) Following the procedure of Example 23 but substituting an equivalentamount of the 2-bromophenethyl mercaptan for the 2-bromophenethylalcohol, there is obtained the desired5,10,12,l3-tetrahydrodibenz[c,f][1,5] thiazonine-S-carboxamide.

EXAMPLE 25 8-chloro-5,6,12,13-tetrahydrodibenz[b,f] [1,5]oxazonine-S-carboxamide Following the procedure of Example 21 butsubstituting an equivalent amount of ethyl 5-chlorosalicylate for theethyl salicylate, there is obtained8-chloro-5,6,12,13-tetrahydrodibenz[b,f] [1,5 ]oxazonine-S-carboxamide.

EXAMPLE 26 9-dimethylsulfamoyl-5,6,12,13-tetrahydrodibenz[b,f] 1,5oxazonine-S-carboxamide Following the procedure of Example 21 butsubstituting an equivalent amount of ethyl4-dimethylsulfamoylsalicylate, there is obtained9-dimethylsulfamoyl-5,6,12,13- tetrahydrodibenz [b,f] [1,5oxazonine-S-carboxarnide.

EXAMPLE 27 9-methylsulfonyl-5,6,12,13-tetrahydrodibenz [b,f] [1,5thiazonine-S-carboxamide Following the procedure of Example 21 butsubstituting an equivalent amount of ethyl4-methylsulfonyl-Lmeroaptobenzoate for the ethyl salicylate, there isobtained the desired 9-methylsulfonyl-5,6,12,13 tetrahydrodibenz[b,f][1,5]thiazonine-S-carboxamide.

19 EXAMPLE 2% 7-fluoro-5,10,12,13-tetrahydrodibenz[c,f] [1,5]oxazonine-5-carboxamide EXAMPLE 297-fluoro-5,10,12,13-tetrahydrodibenz[c,f] [1,5] thiazonine-S-carboxamideFollowing the procedure of Example 23 but substituting an equivalentamount of 4-fluoro-o-nitrobenzyl bromide for the o-nitrobenzyl bromide:and an equivalent amount of o-bromophenethyl mercaptan for theo-bromophenethyl alcohol, there is obtained the desired7-fluoro-5,l0,12,13-

tetrahydrodibenz[c,f] 1,5] thiazonine-S-carboxamide.

What is claimed is: 1. A compound of the formula and salts thereofwherein R is selected from the group consisting of hydrogen, loweralkyl, and phenyl, monoand di-lower alkylphenyl, lower alkoxyphenyl randhalophenyl; R and R taken separately, are each selected from the groupconsisting of hydrogen, lower alkyl, and phenyllower alkyl; NR R takentogether is a heterocyclic radical selected from the group consisting ofpiperidino, pyrolidino, piperazino, N -(lower alkyl)piperazino, N-(hydroxy-lower alkyl)-piperazin0, and morpholino; R and R are eachselected from the group consisting of hydrogen, halogen, lower alkyl,trifiuoromethyl, lower alkoxy, lower alkylsulfonyl, amidosulfonyl, andN,N-di-lower alkylamidosulfonyl; X is selected from the group consistingof oxygen and sulfur; m is 0 to 1, n and p are each 0 to 2, the sum ofm+n+p being 1 to 3, provided that when n is 2, at least one of m' and pis other than 0 and m, n and p do not each represent 1.

2. A com-pound according to claim 1 wherein m is 1, n is 0, and p is 1.

3. A compound according to claim 2 having the name 11,12-dihydro-6H-dibenzo [b,f] [1,4]thiazocine-12-carboxamide.

4. A compound according to claim 2 having the name 2chloro-11,12-dihydro-6H-dibenzo[b,f] [1,4]thiazocine- IZ-carboxamide.

5. A compound according to claim 2 having the name 11,12dihydro-2-(trifluoromethyl)-6H-dibenzo [b,f] [1,4]thiazocine-12carhoxamide.

6. A compound according to claim 1 wherein m is 1, and n and p are each0.

7. A compound according to claim 6 having the name 8 chloro10,11-dihydrodibenzo[b,f] [1,4]thiazepine-10- carboxamide.

8. A compound according to claim 1 in which n is 1 and p and m are both0.

9. A compound according to claim 8 having the nameS,1l-dihydrodi-benz[b,e] [1,4] oxazepine-S-carboxamide.

10. A compound according to claim 8 having the name 7 chloro5,11-dihydrodibenz[b,e][1,4]oxazepine-S-carboxamide.

11. A compound according to claim 8 having the name5,11-dihydrodibenzo[b,e] [1,4] thiazepine-S-carhoxamide.

12. A compound according to claim 1 wherein m is 1, n is 2 and p is 0.

13. A compound according to claim 1 wherein m is O, n is 1 andp is 2.

14. A compound of the formula and salt thereof wherein R is selectedfrom the group consisting of hydrogen, chlorine, and trifluoromethyl.

I References Cited UNITED STATES PATENTS 3,259,631 7/1966 Yale et a1260--295 JAMES A. PA'ITEN, Primary Examiner.

US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 ,452,046 June 24 1969 Harry L. Yale et a1.

It is certified that error appears in the above identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 1, line 27, cancel "NR R line 61, "(Z-dimethylaminoethyl)" shouldread (2-dimethylaminoethoxyethyl) Column 3, formula (IV), that portionof the formula reading @11 should read R4 formula (V) that portion ofthe formula reading should read formula (VI) that portion of the formulareading 2 4 HO C R4 should read Column 6, line 32, "z-ethylphenyl"should read Z-ethylphenol Column 7, formula (XXIV), that portion of theformula reading 3 G should read 9 R4 formula (XXV) that portion of theformula reading NN NH 2 should read 2 same column 7 line 61 "haobenzyl"should read halobenzyl Column 9 line 2 "aminobenzenethio" should readaminobenzenthiol line 20 "hydropolyzed" should read hydrolyzed line 22"dihydrodibenzene" should read dihydrodibenzo Column 12 line 2 "oxazone"should read oxazonine Signed and sealed this 24th day of March 1970.

(SEAL) Attest:

EDWARD M.FLETCHER,JR.

Attesting Officer Commissioner of Patents WILLIAM E. SCHUYLER, JR.

1. A COMPOUND OF THE FORMULA